Nutrigenomics and Pharmagenomics: Hope for the Future

FDA sees need and moves quickly to facilitate by establishing the Division of Personalized Nutrition and Medicine.

The brave new world of nutrigenomics is growing at an exponential rate. Some scientists are claiming nutrigenomics is the most important development in nutrition in almost a century.

It has already caused a paradigm shift in our approach to nutrition and health. On July 1, 2003, the then Commissioner of the Food and Drug Administration (FDA), Dr. Mark B. McClellan, told the Harvard School of Health, “There is a small but growing field called ‘nutrigenomics’ that is seeking to combine the increasing insights from genomics to our understanding of how dietary choices affect our health. Nutrigenomics envisions a future in which personalized genetic profiling takes the guesswork out of deciding what you should eat. By adjusting nutrient composition in a person’s diet according to genetic profiles, gene-based nutrition planning could one day play a significant role in preventing chronic disease.”

In October 2006, the FDA created the Division of Personalized Nutrition and Medicine. Just last fall, the current Commissioner of Food and Drugs, Dr. Andrew C. von Eschenbach stated in the FDA Strategic Plan, “FDA will explore novel scientific approaches (e.g. nutrigenomics) to better understand how the unique attributes of individuals affect the assessment of safety of foods, food components, nutrients and dietary supplements.”

One of the leaders and facilitators of this new field of Nutrigenomics is Jim Kaput, Ph.D., Director of the U.S. Food and Drug Administration’s (FDA) new Division of Personalized Nutrition and Medicine. However, catching up with one of the busiest persons in the world is not an easy task. Fortunately, I was able to chat with Dr. Kaput in late June while he was between assignments on a long-distance flight. In this interview, Dr. Kaput’s views are his own personal views and he is not representing the views of the FDA.

On November 9, 2007, Dr. William Slikker, Jr., the Director of the National Center for Toxicological Research (NCTR) of the Food and Drug Administration announced that Dr. Kaput had been selected as Director of the Division of Personalized Nutrition and Medicine of the NCTR/FDA. Dr. Kaput earned his Ph.D. in the Biochemistry & Cell and Molecular Biology Program, Colorado State University, and performed his Postdoctoral Fellowship in Cell Biology at The Rockefeller University under the direction of Günter Blobel (1999 Nobel Laureate in Physiology and Medicine). Dr. Kaput went on to become an Assistant Professor, Laboratory of Cell Biology, The Rockefeller University and, later, Assistant Professor, Department of Biochemistry, University of Illinois, College of Medicine. After providing guidance and scientific leadership for several private nutritionally related companies, Dr. Kaput was most recently an Assistant Professor, Department of Surgery, University of Illinois, Chicago, and Coordinator, Science and Administrative Activities, Section on Cellular and Molecular Biology, Center of Excellence in Nutritional Genomics, University of California, Davis.

Dr. Kaput is well-published in the area of Nutrigenomics and is frequently asked to present his views to both national and international audiences. He has developed extensive course material and electronic delivery options for both literature reviews and educational materials related to nutrition, genetics, and their relationship. He is also active in the leadership of several national and international societies focused on nutrigenomics. As an example of his international leadership and recognition, Dr. Kaput has just completed his service in South America (Brazil) as a Fulbright Senior Specialist Fellow in Global/Public (nutrigenomics) before accepting his position with NCTR of the FDA.

Passwater:Why did you become a molecular biologist? What aroused your interest in this field?

Kaput: My original intent was to become a physician. The post-WWII baby boom that produced 5–7 applicants for each slot in Illinois medical schools in the early 1970s and an attitude that studying for grades was not as important as learning the material had the fortunate outcome of opening a different route to the same goal: understanding health and disease processes through research. The exact discipline to which I was attracted was biochemistry (my Ph.D. is in biochemistry from Colorado State University under an insightful scientist and warm person, Dr. Tom Sneider) because it had the mix of existing knowledge to learn and taught the tools to explore unanswered questions in a rigorous manner. Modern molecular biology (the cloning era) began just as my graduate career was in full swing and my view was that it was another tool to master. My view of doing science is somewhat old fashioned and follows from my graduate (Dr. Sneider) and postdoctoral advisors (Dr. Gunter Blobel, Nobel Laureate in 1999); they led by doing research on a biological problem using any method or technology necessary rather than find the problem that can be researched with one tool (the “I have a hammer. Where are the nails?”). The result may be a jack-of-all-trades and master of none, but my view is that we need scientists who know how to integrate data from various disciplines.

Passwater:A point well taken. Nutrigenomics, like the new field of nanotechnology, involves innovative and multidisciplinary approaches. Why did you choose the University of California at Davis for your research?

Kaput: A quirk of fate. I was employed by a start up biotechnology company that had the most complete databases of curated genomes—I traveled the country to explain the use of the databases. On one of those trips, I presented a seminar to the Western Human Nutrition Research Center (WHNRC) at UC Davis. In the audience was Dr. Ray Rodriguez, a professor of genetics, who was organizing a multicenter grant focused on nutritional genomics and health disparities.

Passwater:Oh yes, he is the co-author of your book, Nutritional Genomics (Wiley 2006).

Kaput: Ray hired me to help assemble projects from 22 scientists at UC Davis, WHNRC and the Children’s Hospital of Oakland Research Institute into a coherent NIH grant application. This grant was funded and provided me a part-time position under the auspices of the grant. Nancy Fogg-Johnson, Terry Carlone and I also formed NutraGenomics, which was essentially a consulting company since we wanted to be a science-based nutritional genomics company. A physician–scientist at the University of Illinois Chicago, Amelia Bartholomew, M.D., also arranged a position in her laboratory to collaborate on type 2 diabetes and end-stage renal disease. The Nutrigenomic Organization of Europe also provided some salary support to help build the international nutrigenomic society. I may have been the only scientist in nutrigenomics supported by multiple institutions on two continents!

Passwater:What drew you to nutrigenomics?

Kaput: My first collaborator on this project, Dr. Willard Visek, M.D., Ph.D., a titan in nutritional sciences, would stop at my office at the University of Illinois Urbana-Champaign on the way to his (he was an office away) and say (paraphrasing), “You’re going to teach me molecular biology, because if nutritionists don’t get better data, the discipline will die.” Since I was an untenured assistant professor in the biochemistry department, I did not immediately jump at that offer. However, I realized that the emerging tools of molecular biology could indeed be used to analyze nutrient–gene interactions. At about the same time that our first graduate student, Tim Elliot, was starting these experiments (~1986), other transgenic mice experiments showed that oncogenes produced different outcomes in different mouse strains. Those results led to the concept that different genetic make-ups would respond differently to the same diet and produce, or not produce, disease. Given the work of Dr. Charles Scriver (of phenylketonuria [PKU] fame and nutrigenomic pioneer in Canada) and other geneticists, this concept was not unique. However, the strategy of identifying the underlying causal genes may be: comparing gene expression (or metabolite or protein levels) among two or more strains of mice that differ in response to the same diets. Only differences in gene expression could produce a different phenotype (disease or not) based on diet. We are still using that comparative model in both mice studies and, with modifications, in humans. It was only after many years of work in the “pre-Internet” era that I ran across Roger Williams classic book, Biochemical Individuality, which essentially laid out the entire framework for nutrigenomics.

Passwater:Many of our readers are very familiar with the teachings of Dr. Williams. The principles of Biochemical Individuality have been discussed many times in this column.

Kaput: His work, of course, has roots going back to Hippocrates (let food be your medicine and medicine your food). Modern nutrigenomic researchers are really only adding the molecular and genetic data to concepts that are millennia old.

Passwater:Just what are nutrigenomics and pharmacogenomics and why are they important to our health?

Kaput: Living organisms have to respond to their environments; if they don’t, they either die off or move to a new environment—theories and concepts first codified by Darwin. Food is a complex mixture of nutrients and bioactive chemicals. The distinction is that bioactive chemicals are not metabolized for energy but alter the expression of genetic make-up, whereas many nutrients are metabolized for energy and also may alter the expression of genetic make-up. Although most drugs are single chemicals, they still act on and are metabolized by an individual’s genetic make-up—just like chemicals in food. The difference, of course, is that the single chemical is given in high doses and the intended effect differs from the chemicals in food, which are usually at lower doses. Nutrigenomics and pharmacogenomics (and toxicogenomics) are based on the same concept: chemicals from outside the body interacting with and altering biology. We argue that pharmacogenomics must also analyze nutrient intakes because a person’s diet will alter the efficacy of the drug by altering processes involved in adsorption, distribution, metabolism and excretion. Many drug design strategies do not consider nutrition during the 8–10 years of development—and it is little wonder that we have adverse drug responses in the general population (in some cases, one can predict drug–food interactions, and the 13th or 14th edition of Food–Drug Interactions is available. Much of that information came from events AFTER the drugs were released).

Nutrient assessments should be a part of the drug discovery process to determine how efficacy is altered by diet and genetic make-up. The corollary applies: the healthcare team should include a nutritionist who helps assess how drugs will affect an individual’s drug responsiveness. The implications of this concept are far-reaching: nutritional and genetic concepts must be applied in drug research through pharmacists to healthcare teams—a daunting educational task in an era of specialization.

Passwater:You have developed five fundamental precepts of nutrigenomics that have been well-accepted. What are they?

Kaput: As I see it, the five guiding precepts for nutrigenomics are:
• Common dietary chemicals act on the human genome, either directly or indirectly, to alter gene expression or structure.
• Under certain circumstances and in some individuals, diet can be a serious risk factor for a number of diseases.
• Some diet-regulated genes (and their normal, common variants) are likely to play a role in the onset, incidence, progression and/or severity of chronic diseases.
• The degree to which diet influences the balance between healthy and disease states may depend on an individual’s genetic makeup.
• Dietary intervention based on knowledge of nutritional requirement, nutritional status and genotype (i.e., “individualized nutrition”) can be used to prevent, mitigate or cure chronic disease.

The fundamental concepts of nutrigenomics simply summarize hundreds of experiments and concepts dating back to Hippocrates. We wanted to create short statements of the key points to condense the concepts, and they are self-explanatory. The only one that may need additional comments is number three. The focus of much biomarker research, regardless of whether it is gene-based, transcript (mRNA)-based, protein or metabolite, is to link some biological marker to disease or disease susceptibility. This is crucial, but to understand nutrient–gene interactions that result in health or disease, we need to identify the causal genes. Many genes will be affected by the initial changes, but to “treat or prevent,” we need to know the genes that initiate the process.

Passwater:How do you see these five precepts of nutrigenomics in terms of how they impact the concept of RDA and Dr. Roger William’s Biochemical Individuality?

Kaput: Basically, the precepts of nutrigenomics teach us that different individuals may require different levels of micronutrients—this is a concept entirely consistent with William’s “genotrophic” concept. His insights were remarkable given the state of the science of the time.

Passwater: You speak and write of “personalized nutrition and medicine.” Is it really that and just how important is it?

Kaput: To some extent, we already have personalized medicine. Ask almost any physician that has to treat a chronic disease, such as type 2 diabetes, and they will relate specific examples of individuals not responding to one drug, but being helped by another, or not helped at all. Physicians tailor their treatment to each patient. However, they are doing so based on sound knowledge, but also quite a bit of trial and error.
The basic problem we are facing is conceptual: our current biomedical research strategies are based on the average response of a group (population). Nutritional epidemiologists, for example, ask, “What are the average nutrient intakes in healthy people versus those with a chronic disease?” Nutrients consumed more frequently in the case group are associated with disease (although cause and effect cannot be ascertained by these methods). Similarly, genetic epidemiologists ask, “Does the variant of gene X appear more frequently in the case population than the control population?” In both cases, the analyses provide a population average risk (called population attributable risk). This risk may or may not apply to any individual—for example, me—because my genetic make-up, diet and activity levels (and other environmental variables) were not included in the study population. Even if one were to be in the population study, no one is average because of our unique genetic make-up and lifestyle. Drug research is done the same way. While these population risk factors can provide guidance (and I use them), they are guestimates for any individual.

We are building a conceptual and methodological approach to this problem of population averages at the FDA/National Center for Toxicological Research and internationally. The concept is based on the fact that Western-style science has typically been done in Europeans or their descendents (European Americans) and, more recently, other ancestral groups. However, most studies are done in isolation and results are difficult to analyze together. This means we do not know the entire phenotypic or metabolic spectra of human physiology. An easy example is skin color: if you only studied individuals in Iceland, one would conclude that all humans are pink. However, if we could line up everyone (or representatives of groups) from pink to the darkest brown, we would then see the whole range of skin pigmentation. We have not done that yet for metabolism, although we do know that when individuals migrate to new environments, their first- and second-generation descendents adopt the diet and the diseases of their new home country. We intend to collaborate with others around the world to determine the metabolic ranges of humans. It is likely that the first set of data will create groups of individuals who share similar metabolic profiles and there will be a mix of colors in each metabolic group (because of how genetic variation occurs around the world). “Binning” people will provide “group” nutrition—and individuals in the group can personalize by taking vitamins or minerals.

Passwater: What was your role at the UC Davis Center of Excellence in Nutritional Genomics?

Kaput: My official role was a researcher in the High Speed Computing and Informatics group. My unofficial role was to help where needed.

Passwater: You have been a leader in nutrigenomics in several ways, in addition to your research. I have belonged to your Nutrigenomics Alerts forum (Nutrigenomics News & Views) for quite a while and have learned much through it. What led you to start this forum and how has it contributed to this growing science?

Kaput: I think a better description is that I am a worker bee; my intent is to enable more individuals to think about the association among lifestyle factors (e.g., diet, activity, etc.) and genetic makeup. The Alerts forum was started because I was reading published reports in a variety of disciplines and thought my colleagues and friends would help me learn what the articles meant through e-mail exchanges (this was before blogs became ubiquitous). The exchanges are limited (some listers do write to provide their opinion, and I forward the more thoughtful ones to the Alert subscribers). Instead of the exchange, individuals forwarded the e-mails to colleagues and friends and the list has grown organically to over 2,000 subscribers in 50 countries. Since it was started in July 2002, almost one person per day has signed up and stayed on. Compared with www.MoveOn.org, that is a trivial number, but many of the postings are for us science geeks.

The concerted effort I made from the inception of the list to now is to send out e-mails on all aspects of nutrigenomics, which include not only the science of nutrition, genetics, physiology, pathologies, informatics, computation and technologies, but also how the science may be applied in society. For example, nutrigenomics concepts and results may directly address health and healthcare disparities since gene–nutrient interactions may differ among individuals of different ancestral groups (this we know) and in different cultures. We now realize that our research efforts must include populations not normally studied in our research; the benefits of the nutrigenomic research may differ slightly depending on ancestral background and culture. We will not know of these differences without including those who have been left out of the research studies.

Connecting science to that societal issue (health disparities) leads to articles about the food scarcity in developed and developing countries, how the built environment can alter access to healthy foods and activity opportunities, and the ethics of not only conducting the research, but also the implications for applying the knowledge to society. Additional issues that arise are the privacy of genetic and nutrigenomic testing results in research studies and when the results are applied in the clinic, the availability of benefits to the socioeconomically disadvantaged or the cost of specialty food products for optimizing health (food science). We also believe that nutrigenomics will be evidence-based strategies for providing the appropriate foods to individuals with different genetic make-ups—a particularly important goal for eliminating poverty and the consequences for each generation.

Reading and reporting these disparate studies and ideas provides my education in the science and the application. More importantly, I hope that some of the e-mails spark new ideas among basic scientists as well as those who apply the research to challenges facing society.

Passwater: You have also helped organize and promote scientific sessions on genomics such as the Bruce Ames International Symposium on Nutritional Genomics. How and why did these sessions come about?

Kaput: Nutrigenomics is the combination of different disciplines. Our educational system has evolved to “silo” knowledge. Hence, a geneticist might not be exposed to nutritional research concepts, and similarly, nutritional scientists may not meet a gene during their training. One of the main efforts of those of us who began this research before the human genome project was to learn how to communicate to scientists in different disciplines. This still continues. The genomics and nutrigenomics conferences are all designed to improve communication among disciplines that necessarily have to interact and collaborate with each other.

Passwater: What have been the results of these meetings?

Kaput: The international community of scientists, ethicists, policy makers, commercial partners and government agencies interested in nutrigenomics research and applications is now connected and continues to grow. We are now poised to develop productive collaborations with all stakeholders to bring the research to fruition. These meetings have spawned the formation of the Nutrigenomics Society in 2008. This international society for fostering the development of the field will help organize more workshops for formulating specific, harmonized experiments to analyze nutrient–gene interactions in populations around the world.

Passwater: In October 2006, the FDA/National Center for Toxicological Research in Jefferson, AR., created the Division of Personalized Nutrition and Medicine. Science advances and eventually ethics and law respond. Usually people and agencies react only after a near-crisis arises. Here, a government agency has moved in the absence of a crisis to facilitate. So much needs to be done (organization, funding, etc.) to do so. It’s a huge task and there are competing needs. How did this come about?

Kaput: Through the insight of Dr. William Slikker, director of the FDA/National Center for Toxicological Research (NCTR) in Jefferson, AR, his divisional directors and senior administrators, and the commissioner of the FDA. The stroke of genius was that they merged the former Biometry and Risk Assessment Division (statisticians) and the Pharmacogenomics Branch to foster the interactions between basic scientists and mathematicians. The goal of the Division of Personalized Nutrition and Medicine is to create the strategies and methods for moving the field of nutrigenomics from the population-based studies to personalized research and applications. A big task, but a critical one; although food safety remains a critical issue for our country, more people die, more healthcare funds are expended, and our economy is more affected by chronic diseases that can be prevented by optimizing nutrition and lifestyle choices. While the current recommendations are as good as we have now, the new science of nutrigenomics, based squarely on existing knowledge and progress in both nutrition and genetics, will provide more specific information for each individual. A key aspect of this knowledge is that each individual can decide how to apply it to his or her life—a personal choice. We also expect that food manufacturers will incorporate the knowledge into healthier food products. With the growth of the world population, we will likely rely upon manufactured foods for some of our nutritional needs. These need to be healthier and provide better and balanced nutrition.

Passwater: What is the mission of the Division of Personalized Nutrition and Medicine (DPNM)?

Kaput: The DPNM at the FDA/NCTR is charged with developing strategies, methods and resources for improving individual and public health. The need for this new division and research paradigm resulted from the human genome and HapMap projects. These international efforts laid the foundation for one of the most significant scientific contributions to humankind—an evidence-based understanding that while humans are genetically similar, each retains a unique genetic identity that contributes to the wide array of biochemical, physiological and morphological phenotypes in human populations. Parallel molecular genetic studies have demonstrated that nutrient and environmental chemicals directly or indirectly regulate the expression of one’s genetic make-up.

While the research strategies of the 20th century yielded data and knowledge that extended our average life spans and improved personal and public health, much of that knowledge was based on the average response of a population to a food, nutrient or environmental chemical or the average risk for carrying a specific allele of a gene involved in disease. Such knowledge may or may not be applicable to an individual with different genotypes or environmental exposures.

The overall goals of the DPNM are to develop research strategies that account for genetic, environmental and cultural diversity that influences expression of genetic make-ups and produce knowledge for improving personal and public health.

These overarching goals will be met with three parallel efforts that develop:
• integration of “omics” methodologies to assess an individual’s health status and, as importantly, susceptibility to specific chronic conditions influenced by environmental factors including diet,
• a means to capture and assess an individual’s nutritional, environmental and activity exposures, and
• classification algorithms that integrate the data from “omics” and environmental assessments that will result in evidence-based, validated biomedical decision making.

Passwater:How do we best convert the new science of nutrigenomics to practical benefit?

Kaput: This is an active and open challenge to the field. We still do not know how nutrigenomics will be converted to healthcare or personal nutrition and health, although most of us believe there will be benefits. These include optimizing personal health, improving clinical care (introducing nutrition into the physician’s office), better manufactured foods and so forth.

Passwater:Your book stated, “The optimal diet for one individual in a population will not be the same for every individual in that population. The age of personalized diets has arrived, if not in practice, at least in research.” Has nutrigenomics arrived? If not, how soon will it be before it does so?

Kaput: Yes! Nutrigenomics has arrived. PKU testing has been done since the 1960s. California tests for over 40 metabolic diseases, many of which are related to nutrient intakes. We next will focus on chronic diseases, and that process will require 5–10 years.

Passwater:What do you see for the future of this field?

Kaput: Optimized nutrition for everyone. This will likely occur in steps: (i) to create metabolic groups for macronutrient needs, (ii) to optimize individuals’ micronutrient levels. This will improve healthcare if we can begin influencing parents to provide better nutrition and food habits for their children. This goal is particularly important for individuals in the developing world or in socioeconomically disadvantaged populations in the developed world: kids who do not receive the proper nutrition at key developmental stages (in utero and postnatal) never reach their full physical and mental development. While nutrition will not solve the world’s problems, every individual has the right to better and hopefully optimal nutrition for health. This is our responsibility and duty and is consistent with the UN’s Millennium Development Goals. The consequences of this knowledge impact not only healthcare, but also food production and processing—the world needs healthier processed foods. Scientists examining activity and its effect on genetic make-up and health will likely provide similar data for improving the built environment. Providing a safe environment with parks and neighborhoods that encourage activity of adults and kids will be a significant benefit in improving health that will be less expensive than healthcare costs of treating sick citizens. As I heard at one food–health conference in Alberta, Canada, we have to make health the easy choice.

Passwater: Where can our readers find more information on this new field and the new FDA office?

Kaput: The Nutrigenomics Alerts and the www.NuGO.org Web site. We are still creating our FDA/NCTR Division of Personalized Nutrition and Medicine Web site.

Passwater:Thank you, Dr. Kaput, for informing us about the important new field of nutrigenomics and the mission of FDA’s Division of Personalized Nutrition and Medicine. I’ll remind readers again that the views of Dr. Kaput are his own personal views and he is not representing the views of the FDA.WF

Dr. Richard Passwater is the author of more than 40 books and 500 articles on nutrition. He is the director of research and development for Solgar Vitamin and Herb, Inc. Dr. Passwater has been WholeFoods Magazine’s science editor and author of this column since 1985. More information is available on his Web site, www.drpasswater.com.

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